Schultz et al. BMC Medical Genetics(2020) 21:237
https://doi.org/10.1186/s12881-020-01171-2

RESEARCH ARTICLE

Open Access

Two novel mutations in the DNAH11 genein primary ciliary dyskinesia (CILD7) withconsiderable variety in the clinical andbeating cilia phenotype
Rüdiger Schultz1* , Varpu Elenius2, Heikki Lukkarinen2 and Tanja Saarela3

Abstract
Background: Diagnosis of primary ciliary dyskinesia (PCD) still remains a challenge, especially with mutations in the
Dynein Arm Heavy Chain 11 (DNAH11) gene. Classical diagnostic measures like Transmission Electron Microscopy(TEM) are not applicable for mutations in the DNAH11 gene since ultrastructural defects of the ciliary apparatus areabsent. Novel mutations encoding for PCD appear all the time with considerable variation in the clinical picture,making it necessary to update data bases and guidelines for PCD diagnostics.
Methods: In this study we examined two unrelated, Finnish families with symptoms of PCD applying the clinicalscoring system: Primary ciliary dyskinesia Rule (PICADAR), high speed video microscopy analysis (HSVMA) for ciliary
movement, a commercially available gene panel analysis and nasal Nitric Oxide (nNO) measurements if applicable.
Results: Two, likely pathogenic variants in the DNAH11 gene (c.2341G > A, p. (Glu781Lys) ja c.7645 + 5G > A) weredetected. In the first family, compound heterozygous mutations led to disease manifestation in two of 4 children,which showed a similar phenotype of cilia beating pattern but marked differences in disease severity. In the second
family, all three children were homozygotes for the c.2341G > A p.(Glu781Lys) mutation and showed a similar
degree of disease severity. However, the phenotype of cilia beating pattern was different ranging from stiff, static
cilia to a hyperkinetic movement in one of these children.
Conclusions: In this study we describe two Finnish families with PCD, revealing two novel mutations in the
DNAH11 gene which show considerable variety in the clinical and beating cilia phenotype. The results of this study
show the clinician that PCD can be much milder than generally expected and diagnosis demands a combination of
measures which are only successful in experienced hands. Chronic and repeatedly treated wet cough should raisesuspicion of PCD, referring the patient for further diagnostics to a specialised PCD centre.
Keywords: PCD, DNAH11 gene, Compound heterozygosity, PICADAR, Combined diagnostics, Mild disease* Correspondence: rudiger.schultz58@gmail.com
1
Tampere University Hospital, Allergy Centre, PB 2000, 33521 Tampere,
Finland
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Schultz et al. BMC Medical Genetics(2020) 21:237

Page 2 of 7

BackgroundPrimary ciliary dyskinesia (PCD) is an inherited, genetically and clinically heterogeneous disorder which causes
disturbances in the movement of beating cilia. In thesinobronchial epithelium PCD leads to impaired mucociliary clearance. Affected patients suffer from chronic
upper and lower respiratory tract infections which maylead in later life to the development of bronchiectasis
and serious damage to the lungs [1]. Prevalence of PCD
is estimated to be in the range of 1:4000 to 50.000. Thisgap of disease prevalence probably reflects rather the
impaired availability of proper diagnostics than variability of genetics among different ethnic groups [2]. However, some degree of variability can be explained by ahigher prevalence in societies with a high degree of
consanguinity [3].
Over 300 genes are involved in the function andmorphology of the ciliary apparatus, from which at least
40 mutations of genes are known to be disease-causing[4]. However, currently one third of patients with PCD
have no mutations in these genes [5]. The DNAH11
gene encodes for an axonemal outer dynein arm heavy
chain that is expressed primarily in the lungs [6]. Mutations in this gene are associated with PCD but normal
cilia ultrastructure [7, 8]. Like most known ciliary disorders, mutations in the DNAH11 gene are inherited in an
autosomal recessive trait.
The clinical phenotypes of DNAH11 mutations are
similar to other mutations causing PCD, including mild,transient tachypnoea, persistent rhinitis or a blocked
nose in the neonate period leading often to feeding difficulties. During childhood, the development of chronic
middle ear infections and rhinosinusitis is the prominent

feature of the disorder, accompanied by a typical chronic,
wet cough due to persistent, bacterial bronchitis. In adulthood, the same symptoms persist but increasingly consolidations, atelectasis and bronchiectasis appear in HRCT
investigations and bronchial colonisation of Pseudomonas
aeruginosa may be present [9]. Patients of both genders
may also suffer from sub- or infertility [7]. Only 40–50%
of patients present with situs inversus or heterotaxy [10].
Patients with PCD are still underdiagnosed or diagnosed too late [2]. The clinician therefore should also
be aware of atypical phenotypes. Tools like the PICADAR questionnaire may help to raise the level ofsuspicion. In the past, electron microscopy has been
the gold standard for the diagnosis of PCD. However,patients who carry DNHA11 gene mutations show thetypical clinical picture of PCD but morphological defects
in the ultrastructure of cilia are absent which demands a
different diagnostic approach. Today a growing number ofcentres use a combined, complementary approach, including measurement of nNO and HSVMA as firstline diagnostics [2, 11].
In this study we describe five patients in two unrelated-, Finnish families from the same area of WesternFinland, which were investigated for PCD on suspicionof one member of each family employing the PICADAR
questionnaire after Behan et al. [12], nNO measurements, HSVMA and genetic testing.

Methods
We examined five children suspicious for PCD from two
families who originate both from the same region inWestern- Finland. Table 1 gives a summary of clinicaland diagnostic findings of our five index patients.

Table 1 Patient Characteristics
No

Gender/Age/
FamilynNO

HSVMA

Genetics (Mutation)

Clinical Picture

PICADAR1

Female/ 10 years
Family 1

73.9–98 ppb

Almost static, minimal,
residual movement or
vibration of cilia tips.

DNAH11:HET c.2341G > A p.
(Glu781Lys) and HET
c.7645 + 5G > A

perinatal onset of rhinorrhea, recurrent
otitis media, wet cough, blocked nose,
rhinosinusitis, asthma bronchiale,
situs inversus

10/14

2

Male/ 16 years
Family 1

301 ppbSlow, stiff anduncoordinatedmovement, low
bending capacity

DNAH11:HET c.2341G > A p.
(Glu781Lys) andHET c.7645 + 5G > A

school-age onset with recurrent
rhinosinusitis and chronic wet cough

3/14

3

Female/ 6 years
Family 2

45.8 ppb

Minimal, residual
ciliary movement

DNAH11:
HOM c.2341G >A p. (Glu781Lys)

early onset and persistent wet cough,perineal rhinitis, recurrent otitis media,
obstructive bronchitis, atopic dermatitis,
egg allergy, allergic asthma bronchiale

4/14

4

Female/ 4 years
Family 2–Hyperkinetic, ineffective
movement

DNAH11:
HOM c.2341G >A p. (Glu781Lys)

early onset recurrent otitis media, wetcough, situs inversus

10/14

5

Female/ 3 years
Family 2–

Minimal, residual
ciliary movement

DNAH11:
HOM c.2341G >A p. (Glu781Lys)

neonatal onset of rhinorrhea, slimy
and persistent wet cough andrecurrent otitis media

6/14

Schultz et al. BMC Medical Genetics(2020) 21:237

PICADAR questionnaire

Patients were interviewed and scored for probable PCD,
using the PICADAR questionnaire (see additional file 1).
Nasal nitric oxide analysis (nNO)For nNO a CLD 88sp analyser equipped with a Denox 88
module for flow control was used (Eco Physics, Dürnten,
Switzerland). If cooperativity was established, three consecutive trials were taken, from which the highest value
was recorded. Nasal nitric oxide analysis was repeated on
two different occasions.

Page 3 of 7

DNAL1, DRC1, DYX1C1, GAS8, HYDIN, INVS, LRRC6,
NME8, OFD1, PIH1D3, RPGR, RSPH1, RSPH3, RSPH4A,
RSPH9, SPAG1 and ZMYND10.
For interpretation of sequence variants, the laboratory
followed the Blueprint Genetics Variant Classification
Schemes modified from the guidelines of the American
College of Medical Genetics and Genomics 2015 [13].
Both families were referred to genetic counselling which
was carried out at the Tampere University Hospital,
Department of Clinical Genetics, by a clinical geneticist.
Thereafter, the parents and asymptomatic siblings were
tested for familial variants-, in the same laboratory.

Collection of respiratory epithelial cells

After a two week course of oral amoxicillin-clavulanic
acid, ciliary cells were obtained by brushing the inferior
turbinate using an interdental brush of 0.6 mm size
(Topdental Products Ltd., England, UK). Several strips ofepithelial, ciliated cells were dropped into an Eppendorf
tube containing the cell nourishing medium DMEM
(Dulbecco’s Modified Eagle Medium, Thermo Fisher
Scientific Oy, Espoo, Finland). The specimen was transported in a cooled container to be analysed two hours
after brushing. Before investigating the beating cilia, themedium was warmed up to 37 °C to mimic an optimal,
in vivo-like environment during analysis.
High speed video microscopy analysis (HSVMA)

The warmed up samples were evaluated under adifferential-interference microscope (Zeiss, Oberkochen,
Germany) at × 1000 magnification and cilia beat wasrecorded with a digital high-speed video (DHSV) camera(Hamamatsu Orca Flash 4.0 Hamamatsu, Japan) with aframe rate of 400 Hz. DHSV video sequences wereplayed back frame by frame and cilia beat frequency(CBF) was determined by calculating the mean of all recorded cilia beat cycles and the cilia beating pattern(CBP) was determined by two independent expert operators. DHSV was repeated on two different occasions.
Genetic testing

The venous blood samples of the Tampere University
Hospital index patients were taken after written informed consent was obtained. The samples were sent toan accredited laboratory (Blueprint Genetics, Espoo,
Finland) for gene panel analysis. Using NGS methods,
the coding regions, splice junctions and selected noncoding, deep intronic variants of 36 genes associatedwith primary ciliary dyskinesia were analysed. The panel(The Blueprint Genetics PCD panel version 3, 2018) included sequence analysis and copy number variation
analysis of the following genes: ARMC4, C210RF59,
CCDC103, CCDC114, CCDC39, CCDC40, CCDC65,
CCNO, CENPF, CFTR, DNAAF1, DNAAF2, DNAAF3,
DNAAF5, DNAH1, DNAH11, DNAH5, DNAI1, DNAI2,

Exclusion of cystic fibrosis

We excluded CF by demonstration of normal sweat
tests. In addition, the PCD mutation panel (Blueprint
genetics, Medical Lab, Espoo, Finland) also covered
frequent CFTR mutations (85% of all CF cases), making
the existence of CF as a comorbidity very unlikely.

Results
Patient 1 and 3 were examined for PCD due to a long
history of wet cough and chronic otitis media. Afterbeing diagnosed positive for PCD, all other family members were investigated too, undergoing anamnestic interviewing, cilia brushings and HSVMA as well as genetic
testing and nNO if applicable. Two of our patients werediagnosed with situs inversus (patient 1 and 4) but noneof the patients developed bronchiectasis resulting partly
in a particularly low score on the PICADAR questionnaire (see additional file 1). Also nasal polyps could not
be detected. Patient 1 and 3 were diagnosed for asthma
bronchiale. All patients had a history of chronic wet
cough but none of the patients suffered from episodes ofpneumonia. Cystic fibrosis (CF) could be excluded bysweat tests, additionally, the PCD mutation panel (Blueprint genetics, Espoo, Finland) also covered frequent
CFTR mutations (85% of all CF cases), making the existence of CF as a comorbidity very unlikely. In family 1
the clinical picture of the patients differed considerably.
While patient 2 had a much milder pathogeny and late
onset disease with mainly recurrent episodes of rhinosinusitis and wet cough, his younger sister (patient 1)
demonstrated typical early onset symptoms of PCD withchronic otitis, rhinosinusitis and chronic wet cough.
Interestingly, in family 1, patient 2 showed normal
values of nasal nitric oxide while his sister (patient 1)
typically displayed with values under 100 ppb. The beating pattern of cilia in both patients of family 1 washighly abnormal. While patient one had static cilia, patient 2 showed minimal, stiff and uncoordinated movement of cilia. The clinical picture of PCD in the patientsof family 2 (patient 3–5) was much more homogeneousthan in family 1. All children had a high morbidity andSchultz et al. BMC Medical Genetics(2020) 21:237

suffered from recurrent otitis media and wet cough.
Patient 5 also presented with neonatal rhinorrhea and a
blocked nose, leading to feeding difficulties straight after
delivery. However, the ciliary beating pattern differed in
the range of almost static, minimal movement (patient 3
and 5) to rapid, hyperkinetic strokes (patient 4). In family 2 only the oldest child (patient 3) was able to performwith nNO measurements and revealed typical low values
as described with PCD (< 50 ppb).
The genetic testing of patients in family 1 revealed two
compound heterozygous variants in the DNAH11 gene:c.2341G > A, p. (Glu781Lys) ja c.7645 + 5G > A (Fig. 1a).

Page 4 of 7

All patients in family 2 were homozygous for the DNAH11
gene variant: c.2341G > A, p. (Gly781Lys, Fig. 1b). There
are 6 adult individuals heterozygous for the missense
variant c.2341G > A, p. (Glu781Lys) in the Genome
Aggregation Database (gnomAD). It is predicted deleterious by in silico predictions (Polyphen, SIFT). The spliceregion variant c.7645 + 5G > A has not been observed in
the gnomAD reference population cohorts. It is predicted
to weaken the adjacent splice donor site in silico predictions (Alamut Splicing). Neither of the variants have beenpreviously reported in the literature of databases (ClinVar[14], HGMD Professional 2020.3).

Fig. 1 a Pedigree of family 1 with one female and one male offspring affected. Two novel mutations were detected in the DNAH11 gene:c.2341G > A p. (Glu781Lys) ja c.7645 + 5G > A, demonstrating compound heterozygosity. b: Pedigree of family 2. All three children (female) wereaffected. The novel mutation c.2341G > A p. Glu781Lys was first detected in family 1. HET = heterozygous DNAH11 gene mutation. HOM =homozygous DNAH11 gene mutation

Schultz et al. BMC Medical Genetics(2020) 21:237

Discussion
Here we describe two novel variants in the DNAH11
gene causing abnormal movement of beating cilia andclinical disease of PCD in two Finnish families, originatingfrom the same area in Finland. The laboratory classified
both variants as likely pathogenic, considering the association between the gene and the patients´ phenotype, rarity
in healthy control populations and in silico predicted
pathogenicity.
The segregation analysis showed that the two variants
occur in trans in the studied individuals (Fig. 1a, b), andthey were identified in trans (Fig. 1a) or homozygous(Fig. 1b) in siblings with the same phenotype. The
heterozygous carriers of the c.2341G > A, p. (Glu781Lys)
variant and the c.7645 + 5G > A variant were healthy andasymptomatic. Thus, the segregation of the variants supported recessive inheritance and pathogenicity of thevariants in both families (Fig. 1a and b).
Consanguinity between the two families could not beestablished. However, all individuals heterozygous for the
missense variant c.2341G > A, p. (Glu781Lys) in the Genome Aggregation Database (gnomAD) were in the Finnish
control population cohort. Since Finland is considered tobe genetically isolated, through the founder effect, the variant c. 2341G > A, p.(Glu781Lys) could be enriched in
Finland [15]. Pathogenic variants of DNAH11 have previously been reported to be truncating (66%) or missense(34%) and have been exclusively seen in patients with aclinical phenotype of PCD, normal ciliary ultrastructure
and recessive inheritance [7, 16]. In the first family (Fig. 1a)
two of 4 children were affected with compound heterozygosity and these patients showed marked variability indisease severity. The clinical course of patient 1 revealed typical features for PCD with perinatal onset andaggravating symptoms during early childhood, whereas
patient 2 had a much milder course of the disease withonset just before school age suffering merely from rhinosinusitis and chronic wet cough. This patient had
also a normal nitric oxide count and would probably
not have been suspicious for PCD on account of his
medical record or PICADAR questionnaire. Because his
sister was diagnosed first, he was investigated like allother family members and appeared positive only
through HSVMA and genetic testing. In the second
family (Fig. 1b) all of their 3 offspring were homozygous for the mutation c.2341 G > A, p. (Glue781Lys)
and had all the same severity of disease. However, during HSVMA the beating pattern differed markedly inthe range of almost static, minimal movement to rapid,
hyperkinetic strokes which is in concert with the observations of Schwabe and Lucas et al. [7, 8]. Only one of
the children of family 2 was cooperative enough toperform in nasal nitric oxide measurements, whichwere characteristically low (< 50 ppb).

Page 5 of 7

Concerning the clinical phenotype of PCD up to 85%
of individuals have a history of neonatal onset with
unexplained respiratory distress and/or rhinorrhea [2].
This is taken into account in the PICADAR questionnaire (see additional file 1) which helps to raise suspicion for PCD in classical cases. If neonatal distress andsitus inversus or heterotaxy are absent the score drops
rapidly which probably draws the patient out of focus
for PCD. Actually, only two of our five patients(patients 1 and 4) received a PICADAR score over 6/
14. Considering further diagnostics TEM is not an
option with mutations in the DNAH11 gene since thisphenotype doesn’t reveal morphological changes of theciliary apparatus. In addition, an increasing number of
PCD variants have been detected (at least 30% of all
PCD variants) with normal ultrastructure of cilia [16,17] questioning the use of TEM in first line diagnostics. Therefore, the use of nasal nitric oxide measurements as the first line diagnostic tool in suspected
PCD has been suggested [11]. Especially in children
this test demands a high degree of compliance and canbe only rarely performed under the age of 6. It has also
been of notice that with mutations in the DNAH11
gene, values of nasal nitric oxide might be in thenormal range, as we have shown to be the case withpatient 2. This has been reported also by other investigators, especially with the hyperkinetic phenotype of
DNAH11 mutations. In addition, false positive results
can also be observed with cystic fibrosis, nasal polyposis and acute upper airway infections [2]. HSVMA isa good choice for first line diagnostics in PCD
although it has its own pitfalls and is valuable only inexperienced hands. Upper airway infections, otherchronic lung diseases like asthma with nasal polyps
and cystic fibrosis have an impact on beating cilia.
Before the patient is investigated, he or she should betherefore treated with an oral course of antibiotics for
two weeks. Most physicians use a broad-spectrum oral
antibiotic like amoxicillin plus clavulanic acid or alternatively a cephalosporin to target the common respiratory pathogens. Normally beating cilia rules out PCD.
In positive cases a second pathological result should be
attained before proceeding to further diagnostics andtreatment. Genetic testing has become easily available
and prices for the analysis are dropping. At the time ofdiagnosis, our panel contained 36 mutations but new
mutations are appearing constantly in the literature. At
the present, approximately one third of diagnosed PCD
patients do not have mutations in the listed genes. We
therefore suggest that in cases suspicious for PCD andregardless of the score in the PICADAR questionnaire,
a combination of diagnostic tools should be used implying HSVMA together with nasal nitric oxide (if possible) and genetic testing.

Schultz et al. BMC Medical Genetics(2020) 21:237

Page 6 of 7

Conclusion
This study identified two novel mutations in the
DNAH11 gene which show considerable variety in theclinical picture of PCD and phenotype of beating cilia.
Therefore, mutations in the DNAH11 gene may constitute a considerable diagnostic challenge with low PICADAR scores, normal values of nasal nitric oxide measurements, hyperkinetic movements instead of static cilia
and normal ultrastructure. This should remind the clinician that the clinical picture of PCD can be much
milder than generally assumed and that for every childwith chronic wet cough, a combination of diagnostic
tools is needed to rule it out, as recommended in a
recent update of guidelines [18].

details and/or clinical images was obtained from the parents. Processing ofpatient data was carried out by following the EU General Data Protection
Regulation (GDPR). Images or personal data which could possibly
compromise the anonymity of our patients was not included.

Supplementary Information

References
1. Bush A, Chodhari R, Collins N, Copeland F, Hall P, Harcourt J, Hariri M, Hogg
C, Lucas J, Mitchison HM, O’Callaghan C, Phillips G. Primary ciliary dyskinesia:
current state of the art. Arch Dis Child. 2007;92:1136–40.
2. Werner C, Grosse Onnebrink J, Omran H. Diagnosis and management ofprimary ciliary dyskinesia. Cilia. 2015;4:2–9.
3. O’CallaghanC CP, Moya E. High prevalence of primary ciliary dyskinesia in a
British Asian population. Arch Dis Child. 2010;95:51–2.
4. Lucas JS, Davis SD, Omran H, Shoemark A. Primary ciliary dyskinesia in the
genomics age. Lancet Respir Med. 2020;8:202–16.
5. Horani A, Ferkol TW, Dutcher SK, Brody SL. Genetics and biology of primary
Ciliary dyskinesia. Paediatr Respir Rev. 2016;18:18–24.
6. Whitfield M, Thomas L, Bequignon E, Schmitt A, Stouvenel L, Montantin G,
Tissier S, Duquesnoy P, Copin B, Chantot S, Dastot F, Faucon C, Barbotin AL,
Loyens A, Siffroi JP, Papon JF, Escudier E, Amselem S, Mitchell V, Touré A,
Legendre M. Mutations in DNAH17 encoding a sperm specific Axonemalouter dynein arm heavy chain, cause isolated male infertility due
Asthenozoospermia. Am J Hum Genet. 2019;105:198–212.
7. Schwabe GC, Hoffmann K, Loges NT, Birker D, Rossier C, de Santi MM,
Olbrich H, Fliegauf M, Failly M, Liebers U, Collura M, Gaedicke G, Mundlos S,
Wahn U, Blouin J-L, Niggemann B, Omran H, Antonarakis SE, Bartolini L.
Primary Ciliary dyskinesia associated with Normal Axoneme ultrastructure iscaused by DNAH11 mutations. Hum Mutat. 2008;29:289–98.
8. Lucas JS, Adam EC, Goggin CL, Jackson CL, Powles-Glover N, Patel SH,
Humphreys J, Fray MD, Falconnet E, Blouin J-L, Cheeseman MT, Bartolini L,
Norris DP, Lackie PM. Static respiratory cilia associated with mutations in
Dnahc11/DNAH11: a mouse model of PCD. Hum Mutat. 2011;33:495–503.
9. Noone PG, Leigh MW, Sannuti A, Minnis SL, Carson JL, Hazucha M, Zariwala
MA, Knowles MR. Primary ciliary dyskinesia: diagnostic and phenotypicfeatures. Am J Respir Crit Care Med. 2004;169:459–67.
10. Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson
BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone
PG, Zariwala MA, Knowles MR. Congenital heart disease and otherheterotaxic defects in a large cohort of patients with primary ciliary
dyskinesia. Circulation. 2007;115:2814–21.
11. Marthin JK, Nielsen KG. Choice of nasal nitric oxide technique as first-line
test for primary ciliary dyskinesia. Eur Respir J. 2011;37:559–65.
12. Behan L, Dimitrov BD, Kuehni CE, Hogg C, Caroll M, Evans HJ, Goutaki M,
Harris A, Packham S, Walker WT, Lucas J. PICADAR: a diagnostic predictive
tool for primary ciliary dyskinesia. Eur Respir J. 2016;47:1103–12.
13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde
M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality
Assurance Committee. Standards and guidelines for the interpretation ofsequence variants. A joint consensus recommendation of the American
College of Medical Genetics and Genomics and the Association for
Molecular Pathology. Genet Med. 2015;17(5):405–24.
14. Landrum MJ, Lee JM, Riley GR, et al. ClinVar: public archive ofrelationships among sequence variation and human phenotype. Nucleic
Acids Res. 2014;42:D980–5.
15. Kääriäinen H, Muilu J, Perola M, Kristiansson K. Genetics in an isolated
population like Finland: a different basis for genomic medicine. J
Community Genet. 2017;8:319–26.

The online version contains supplementary material available at https://doi.
org/10.1186/s12881-020-01171-2.
Additional file 1. PICADAR Questionnaire after Behan et al. [12].
Abbreviations
CILD7: Ciliary Disorder Number 7; PCD: Primary ciliary dyskinesia;
DNAH11: Dynein Arm Heavy Chain 11; TEM: Transmission electron
microscopy; PICADAR: PrImary CiliAry DyskinesiA Rule; CFTR: Cystic Fibrosis
Transmembrane Conductance Regulator
Acknowledgements
First we want to thank our patients and their parents for their great interest,
cooperation and consent to publish this article. Furthermore, we thank Mrs.
Tiina Peromaa (CMT) for excellent technical expertise in processing thesamples for HSVMA. We wish also to thank Mrs. Johanna Juvankoski (PN) for
her help with nasal NO measurements and cilia brushings. Special thanks goout to Mr. Alan Brown for proof-reading the manuscript.
Authors’ contributions
RS as the treating physician carried out the brushings, gathered all patient
data and wrote the manuscript. Genetic counselling of families and expert
advice concerning the genetic data, pedigree figures and corrections of themanuscript were carried out by TS. Analysis of high speed video microscopy
was carried out by HL and VE who both contributed also in writing themanuscript. All authors read and approved the final manuscript.
Funding
For this case report no fund-raising has been carried out and there are nosponsors involved to cover expenses.
Availability of data and materials
All data gathered, analysed and compiled in this study are included in the
manuscript. Patient videos of cilia movement and the Blueprint Genetics
laboratory report are available from the corresponding author on reasonable
request.
Ethics approval and consent to participate
Written informed consent to participate was obtained from all patients. For
patients under 18 years of age written informed consent was obtained fromtheir parents. For ethical approval to investigate PCD cases the study
protocol was submitted to the local Ethical Committee of the Turku
University Hospital for evaluation. Permission was granted under thepermission number ETMK 69–2017.
Consent for publication
For all our patients written informed consent was obtained to publish
clinical details and/or clinical images compiled in this study. For any patientunder the age of 18 written informed consent for the publication of clinicalCompeting interests
The authors of this article have no conflict of interest concerning thispublication.
Author details
1
Tampere University Hospital, Allergy Centre, PB 2000, 33521 Tampere,
Finland. 2Department of Pediatrics, Turku University Hospital,
Kiinanmyllynkatu 4-8, 20520 Turku, Finland. 3Department of Clinical Genetics,
Kuopio University Hospital, PB 1, 70029 Kuopio, Finland.
Received: 31 July 2020 Accepted: 10 November 2020

Schultz et al. BMC Medical Genetics(2020) 21:237

16. Knowles MR, Leigh MW, Carson JL, Davis SD, Dell SD, Ferkol TW, Olivier KN,
Sagel SD, Rosenfeld M, Burns KA, Minnix SL, Armstrong MC, Lori A, Hazucha
MJ, Loges NT, Olbrich H, Becker-Heck A, Schmidts M, Werner C, Omran H,
Zariwala MA. Mutations of DNAH11 in patients with primary ciliary
dyskinesia with normal ciliary ultrastructure. Thorax. 2012;67:433–41.
17. Boon M, Smits A, Cuppens H, Jaspers M, Proesmans M, Dupont LJ,
Vermeulen FL, Van Daele S, Malfroot A, Fodding V, Jrissen M, De Boeck K.
Primary ciliary dyskinesia: critical evaluation of clinical symptoms anddiagnosis in patients with normal and abnormal ultrastructure. Orphanet J
Rare Dis. 2014;9:11.
18. Lucas JS, Barbato A, Collins SA, Goutaki M, Behan L, Caudri D, Dell S, Eber E,
Escudier E, Hirst RA, Hogg C, Jorissen M, Latzin P, Omran H, Papon J-F,
Pohunek P, Redfern B, Rigau D, Rindlisbacher B, Santamaria F, Shoemark A,
Snijders D, Tonia T, Titieni A, Walker WT, Werner C, Bush A, Kuehni CE.
European Respiratory Society guidelines for the diagnosis of primary ciliary
dyskinesia. Eur Respir J. 2017. https://doi.org/10.1183/13993003.01090-2016.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Page 7 of 7